Globally, tuberculosis (Tb) notification data show a male-to-female ratio of 1.7 and higher, but the underlying reasons for the male bias remain elusive. Despite the well-known gender bias in human pulmonary Tb, a majority of experimental animal studies either do not separate and analyze data by sex or do not report the sex of their subjects at all. In the present study, we report increased male susceptibility in one of the most commonly used mouse models for Tb, C57BL/6 mice. Our study revealed that disease progression upon aerosol infection with Mycobacterium tuberculosis (Mtb) was accelerated in males resulting in increased morbidity and mortality compared to females. Elevated Mtb loads in males were associated with an early exaggerated pulmonary inflammatory response which likely was detrimental to the host, as reflected by exacerbated pathology and increased mortality. Our data emphasis the urgent need to include and separately analyze both sexes in future animal studies of Tb in order to appreciate the differences in immune responses and disease pathogenesis between males and females.

Tuberculosis prevalence is significantly higher among men than women. We have previously revealed an increased susceptibility of male C57BL/6 mice towards Mycobacterium tuberculosis (Mtb) H37Rv. In the current study, we confirm the male bias for infection with the Beijing strain HN878. Males succumbed to HN878 infection significantly earlier than females. In both models, premature death of males was associated with smaller B cell follicles in the lungs. Analysis of homeostatic chemokines and their receptors revealed differences between H37Rv and HN878 infected animals, indicating different immune requirements for follicle formation in both models. However, expression of IL-23, which is involved in long-term containment of Mtb and lymphoid follicle formation, was reduced in male compared to female lungs in both models. Our study reveals sex differences in the formation of B cell follicles in the Mtb infected lung and we propose that impaired follicle formation is responsible for accelerated disease progression in males.Tuberculosis (TB) is the most prevalent bacterial infectious disease in humans. The causative agent, Mycobacterium tuberculosis (Mtb), is carried by an estimated 2-3 billion people globally and claims approximately 1.5 million lives each year 1 . The global TB pandemic is characterized by significant differences in prevalence between men and women, reflected by a male-to-female ratio for worldwide case notifications of 1.8 1 . Both gender-and sex-related factors likely contribute to higher TB rates in men, but the role of the latter has been largely ignored 2-5 .We have previously shown an increased susceptibility for male C57BL/6 mice to infection with the laboratory-adapted strain Mtb H37Rv 6 . Accelerated disease progression in males after low-dose aerosol infection resulted in increased morbidity and mortality compared to females. Likewise, a study in BALB/c mice revealed that males are more susceptible to H37Rv infection than females 7 . The fact that two of the most widely used TB mouse models do reflect the global male bias in humans emphasizes the need to include both sexes in basic research and pre-clinical studies.Our observations in H37Rv infected C57BL/6 mice pointed to an impaired formation of lymphoid aggregates in the male lung 6 . In the current study, we substantiate our previous observation and show that B cell follicles that form in the Mtb infected lung were much smaller in males compared to females. Moreover, expression of chemokines associated with the homing of lymphocytes to the infected lung such as CXCL13 and CCL19 was significantly lower in males compared to females, further indicating that B cell follicle formation in response to H37Rv infection is impaired in males.Mtb is a member of the Mtb complex (Mtbc), and Mtbc strains are more genetically diverse than was previously recognized 8 . Importantly, genetic diversity might contribute to clinical, pathogenic, and immunologic heterogeneity in disease progression and outcome. H37Rv was isolated in 1905 and is not a relevant...

The Acknowledgements section in this Article is incomplete. "We thank Doreen Beyer for culturing of Mtb H37Rv, Imke Storm for technical assistance, Johanna Volz for helpful discussions regarding immunohistochemistry and Jochen Behrends and Hannelore Lotter for critical discussions and helpful comments on the manuscript. This work was supported by in-house funding from the Research Center Borstel. " should read: "We thank Doreen Beyer for culturing of Mtb H37Rv, Imke Storm for technical assistance, Johanna Volz for helpful discussions regarding immunohistochemistry and Jochen Behrends and Hannelore Lotter for critical discussions and helpful comments on the manuscript. This work was supported by in-house funding from the Research Center Borstel. The publication of this article was funded by the Open Access Fund of the Leibniz Association. "

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